Responses to central Na+ and ouabain are attenuated in transgenic rats deficient in brain angiotensinogen

Studies with angiotensin (Ang) II type 1 receptor blockers suggest that the brain renin-angiotensin system contributes to sodium-induced sympathoexcit ation and hypertension. To provide mon specific evidence for the involvemen t of Ang II, locally produced in the brain, transgenic rats were used, whic h express an antisense RNA against angiotensinogen mRNA specifically in the brain, reducing angiotensinogen levels in the brain by >90%. In freely mov ing transgenic rats and Sprague-Dawley rats as control animals, blood press ure and heart rate responses to intracerebroventricular infusion (3.8 muL/m in for 10 minutes) of artificial cerebrospinal fluid and Na+-rich artificia l cerebrospinal fluid (containing 0.2, 0.3, and 0.45 mol/L Na+) as well as intracerebroventricular injection of ouabain (0.3 and 0.6 mug/2 muL) were a ssessed. Central infusion of Na+-rich artificial cerebrospinal fluid increa sed blood pressure and heart rate in a dose-related manner. However, the pe ak increases by each dose of Na+ were attenuated by 50% to 70% in the trans genic versus Sprague-Dawley rats. Increases in blood pressure and heart rat e in response to ouabain at both doses were attenuated by 55% to 70% in the transgenic versus Sprague-Dawley rats. In the hypothalamus, Ang I level wa s markedly lower (31 +/-9 versus 76 +/- 13 pg/g, P<0.05) and Ang II level t ended to be lower in the transgenic versus Sprague-Dawley rats, These resul ts indicate that the production of angiotensins in the brain is decreased i n transgenic rats. The attenuated sympathoexcitatory and presser responses to ouabain and Nat-rich artificial cerebrospinal fluid in transgenic rats s upport the concept that the local brain renin-angiotensin system, that is, locally produced Ang II, plays an important role in the sympathoexcitatory effects of ouabain and sodium.